There is considerable epidemiological evidence that hyperinsulinemia may contribute to an absence of sex-related differences in cardiovascular diseases in insulin-resistant humans by reversing normal differences in the vascular actions of sex steroids. Mechanisms for such hormonal interactions are not understood, due in part to lack of their study in animal models. The spontaneously hypertensive rat (SHR) is widely employed in the study of essential hypertension. Two recent studies showed hypertensive responses to chronic insulin administration in male SHR. The mechanism responsible for this may relate in part to an impaired vasodilator action of insulin as seen in the aortic and other arterial tissues of these animals. The applicant's work with male and female stroke-prone SHR suggests to him that the hyperinsulinemia associated with chronic insulin administration may interact with sex steroids to aggravate this impairment, thereby increasing arterial adrenergic contractility and hypertension to a greater degree in females than in males. He has found that chronic administration of glyburide, an insulin secretagogue, significantly increased blood pressure in female but not in male stroke-prone SHR. This increase was accompanied by a substantial increase in circulating insulin and a reversal of insulin's intrinsic action (in vivo) on adrenergic tone in isolated arterial tissue, from an attenuating to an accentuating action. Males did not show these effects and direct administration of glyburide (in vitro) to arterial tissues isolated from female SHR did not produce the same reversal in insulin's intrinsic action. However, in other in vitro experiments he found that low (plasma) levels of estrogen can blunt the attenuating action of a high concentration of insulin on adrenergic tone and high insulin in turn can reverse the normal attenuating action of the estrogen. High insulin also nearly abolished the normal accentuating action of dihydrotesterone on adenergic tone in vitro. Whether these same insulin/steroid interactions operate in vivo to alter development of hypertension is not known but is important to establish before one can justify future efforts to unravel mechanisms responsible for them. The applicant hypothesizes that in individuals genetically predisposed to hypertension with insulin-resistance, chronically elevated circulating insulin will raise blood pressure more in females than in males by 1) aggravating (more in females) a preexisting impairment in the normal intrinsic vasodilator activity of insulin to the point of unmasking (or inducing) an intrinsic vasoconstrictor sensitivity to insulin and/or 2) reversing normal contrasting actions of estrogen and testosterone on arterial contractility. Thus, his specific aims are to determine: 1) if chronic insulin administration accelerates development of hypertension more so in female than male SHR and if this is associated with a greater shift in the intrinsic action of insulin on adrenergically-mediated arterial contraction (a shift from attenuating to accentuating action) and/or reversal of normal sex steroid effects on such contraction; 2) if the sex-related differences in effects of chronic insulin administration in aim 1 (on blood pressure and arterial adrenergic contractile sensitivity to insulin and sex steroids) are abolished by castration and then restored by replacement of estrogen (or estrogen plus progesterone) to female and testosterone to male SHR.